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- PDB-7p9u: Cryo EM structure of System XC- in complex with glutamate -

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Basic information

Entry
Database: PDB / ID: 7p9u
TitleCryo EM structure of System XC- in complex with glutamate
Components
  • 4F2 cell-surface antigen heavy chain
  • Cystine/glutamate transporter
KeywordsMEMBRANE PROTEIN / transporter glutamate cystine
Function / homology
Function and homology information


cystine:glutamate antiporter activity / regulation of neutrophil apoptotic process / L-kynurenine transmembrane transport / L-kynurenine transmembrane transporter activity / regulation of cysteine metabolic process / regulation of glutathione biosynthetic process / regulation of glutamate metabolic process / regulation of melanin biosynthetic process / regulation of AMPA glutamate receptor clustering / L-cystine transport ...cystine:glutamate antiporter activity / regulation of neutrophil apoptotic process / L-kynurenine transmembrane transport / L-kynurenine transmembrane transporter activity / regulation of cysteine metabolic process / regulation of glutathione biosynthetic process / regulation of glutamate metabolic process / regulation of melanin biosynthetic process / regulation of AMPA glutamate receptor clustering / L-cystine transport / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / neutral L-amino acid secondary active transmembrane transporter activity / apical pole of neuron / aromatic amino acid transmembrane transporter activity / tyrosine transport / L-histidine transport / amino acid transport complex / dipeptide import across plasma membrane / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / L-alanine import across plasma membrane / regulation of protein transport / isoleucine transport / phenylalanine transport / methionine transport / L-amino acid transmembrane transporter activity / valine transport / L-leucine transmembrane transporter activity / calcium:sodium antiporter activity / L-leucine transport / thyroid hormone transport / proline transport / L-glutamate transmembrane transport / glutathione transmembrane transport / amino acid transmembrane transport / regulation of cellular response to oxidative stress / ventricular system development / lens fiber cell differentiation / intracellular glutamate homeostasis / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / L-glutamate import across plasma membrane / Tryptophan catabolism / striatum development / astrocyte projection / exogenous protein binding / anchoring junction / limb development / Basigin interactions / negative regulation of ferroptosis / response to redox state / microvillus membrane / NFE2L2 regulating anti-oxidant/detoxification enzymes / lung alveolus development / amino acid transport / regulation of synapse organization / adult behavior / response to exogenous dsRNA / tryptophan transport / glutathione metabolic process / basal plasma membrane / response to nicotine / brush border membrane / modulation of chemical synaptic transmission / visual learning / response to organic cyclic compound / platelet aggregation / response to toxic substance / calcium ion transport / double-stranded RNA binding / melanosome / apical part of cell / virus receptor activity / regulation of cell population proliferation / cellular response to oxidative stress / basolateral plasma membrane / carbohydrate metabolic process / cadherin binding / symbiont entry into host cell / protein heterodimerization activity / apical plasma membrane / lysosomal membrane / synapse / cell surface / protein homodimerization activity / RNA binding / extracellular exosome / nucleoplasm / membrane / plasma membrane
Similarity search - Function
L-type amino acid transporter / Solute carrier family 3 member 2, N-terminal domain / 4F2 cell-surface antigen heavy chain / Solute carrier family 3 member 2 N-terminus / : / Amino acid/polyamine transporter I / Amino acid permease / Alpha amylase, catalytic domain / Glycosyl hydrolase, family 13, catalytic domain / Alpha-amylase domain ...L-type amino acid transporter / Solute carrier family 3 member 2, N-terminal domain / 4F2 cell-surface antigen heavy chain / Solute carrier family 3 member 2 N-terminus / : / Amino acid/polyamine transporter I / Amino acid permease / Alpha amylase, catalytic domain / Glycosyl hydrolase, family 13, catalytic domain / Alpha-amylase domain / Glycosyl hydrolase, all-beta / Glycoside hydrolase superfamily
Similarity search - Domain/homology
GLUTAMIC ACID / Amino acid transporter heavy chain SLC3A2 / Cystine/glutamate transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsParker, J.L. / Deme, J.C. / Lea, S.M. / Newstead, S.
Funding support United Kingdom, 10items
OrganizationGrant numberCountry
Wellcome Trust201536 United Kingdom
Wolfson FoundationWL160052 United Kingdom
Engineering and Physical Sciences Research CouncilEP/L000253/1 United Kingdom
Wellcome Trust209194 United Kingdom
Wellcome Trust100298 United Kingdom
Wellcome Trust219531 United Kingdom
Wellcome Trust215519 United Kingdom
Wellcome Trust219531 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/M011984/1 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/S021043/1 United Kingdom
CitationJournal: Nat Commun / Year: 2021
Title: Molecular basis for redox control by the human cystine/glutamate antiporter system xc.
Authors: Joanne L Parker / Justin C Deme / Dimitrios Kolokouris / Gabriel Kuteyi / Philip C Biggin / Susan M Lea / Simon Newstead /
Abstract: Cysteine plays an essential role in cellular redox homoeostasis as a key constituent of the tripeptide glutathione (GSH). A rate limiting step in cellular GSH synthesis is the availability of ...Cysteine plays an essential role in cellular redox homoeostasis as a key constituent of the tripeptide glutathione (GSH). A rate limiting step in cellular GSH synthesis is the availability of cysteine. However, circulating cysteine exists in the blood as the oxidised di-peptide cystine, requiring specialised transport systems for its import into the cell. System xc is a dedicated cystine transporter, importing cystine in exchange for intracellular glutamate. To counteract elevated levels of reactive oxygen species in cancerous cells system xc is frequently upregulated, making it an attractive target for anticancer therapies. However, the molecular basis for ligand recognition remains elusive, hampering efforts to specifically target this transport system. Here we present the cryo-EM structure of system xc in both the apo and glutamate bound states. Structural comparisons reveal an allosteric mechanism for ligand discrimination, supported by molecular dynamics and cell-based assays, establishing a mechanism for cystine transport in human cells.
History
DepositionJul 28, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 17, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 2, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
A: 4F2 cell-surface antigen heavy chain
B: Cystine/glutamate transporter
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,7763
Polymers125,6282
Non-polymers1471
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area2090 Å2
ΔGint-25 kcal/mol
Surface area24800 Å2

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Components

#1: Protein 4F2 cell-surface antigen heavy chain / 4F2hc / 4F2 heavy chain antigen / Lymphocyte activation antigen 4F2 large subunit / Solute carrier ...4F2hc / 4F2 heavy chain antigen / Lymphocyte activation antigen 4F2 large subunit / Solute carrier family 3 member 2


Mass: 69161.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC3A2, MDU1 / Production host: Homo sapiens (human) / References: UniProt: P08195
#2: Protein Cystine/glutamate transporter / Amino acid transport system xc- / Calcium channel blocker resistance protein CCBR1 / Solute carrier ...Amino acid transport system xc- / Calcium channel blocker resistance protein CCBR1 / Solute carrier family 7 member 11 / xCT


Mass: 56466.605 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC7A11 / Production host: Homo sapiens (human) / References: UniProt: Q9UPY5
#3: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C5H9NO4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: System XC- / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 59.1 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 79698 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0034045
ELECTRON MICROSCOPYf_angle_d0.6675511
ELECTRON MICROSCOPYf_dihedral_angle_d4.849540
ELECTRON MICROSCOPYf_chiral_restr0.043659
ELECTRON MICROSCOPYf_plane_restr0.004666

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